Topical non-aqueous acetic compositions



United States Irving L. Ochs, Annapolis, and Preston L. Veltman, SevernaPark, Md.

No Drawing. Application July 7, 1953, Serial No. 366,631

7 Claims. (Cl. 167-58) This invention relates to substantiallynon-aqueous compositions substantially insoluble in water and capable ofproviding therapeutically useful concentrations of ace tic acid fortreating a variety of infections and potentially infected wounds ofepithelial and other tissues.

Among the objects to the present invention are nonaqueous compositionswhich provide a therapeutic concentration of aqueous acetic acid at theinterface of topical application.

Further objects include such compositions containing normally highlytoxic or caustic materials under control to produce therapeuticallybeneficial materials.

Still further objects and advantages of the present invention willappear from the more detailed description set forth below, it beingunderstood that such more detailed description is given by way ofillustration and explanation only, and not by way of limitation sincevarious changes therein may be made by those skilled in the art withoutdeparting from the scope and spirit of the present invention.

In accordance with the present invention, the necessary control ofaqueous acetic acid concentration is obtained at the tissue interface bycompositions for topical application containing a substance capable ofproducing acetic acid in topically effective concentrations by reactionat the aqueous interface where topical application is effected. Thecompositions are thus suitable for therapeutic use where healing andepithelial growth is the desired objective. Methods of employing whatare normally considered to be dangerous materials, known to be lethal toeven healthy tissue, in a way that results in new and useful therapeuticcompositions is within the scope of the present invention. It has beenfound that substantially non-aqueous systems can be prepared containingsubstantial quantities of, for instance, acetic anhydride. The aceticanhydride is capable of dilfusing thru the mass and at the aqueousinterface provides a source of aqueous acetic acid. In certain instancesit has been found desirable to assist the solution of acetic anhydride(or other active ingredient) by first dissolving the acetic anhydride ina solvent, e. g. a sweet oil (for instance, medicinal olive oil) and,then, compounding this base material with for example petrolatum toobtain a desired composition. A homogeneous, single phase, compositionmay thus be obtained. The same general procedure may be employed usingglacial acetic acid or other active component.

The concentration of acetic acid at the'point of use is a function ofthe concentration of acetic ingredient (i. e., acetic anhydride, glacialacetic acid, or other material) in the non-aqueous medium and it isproportional to the rate of diffusion thru the holding medium to theinterface. The rate of dilution at the interface, rate of diffusionwithin the medium, and mechanical mixing action of the body on thevehicle are also factors to be considered.

An optimum system can be compounded wherein a maximum concentration ofacetic acid producing material atent O 2,788,308 Patented Apr. 9, 1957ice may be contained in the non-aqueous mass and the diffusion factorsregulated to provide a desired rate of production of aqueous acetic acidfor therapeutic purposes. The diflusion rate may be controlled by theaddition of selected agents that may, by their interreaction with theactive ingredient, either, as desired, increase, or decrease, thediffusion rate and thereby influence the aqueous acetic acidconcentration at the interface between the substantially non-aqueousmedium and the tissue surface. The fundamental physical characteristicsof the substantially non-aqueous vehicle may also be selected or alteredto provide a desired physical effect or a. beneficial additionaltherapeutic action.

The active component e. g. one capable of generating acetic acid as byhydrolysis and or dilution at the interface of topical application, isdesirably acetic anhydride or glacial acetic acid or mixtures thereof.These active agents will be utilized to illustrate the invention. Butone may obtain the desired result of providing a therapeutic level ofacetic acid solution at an interface by utilizing molecular compositionscapable of producing acetic acid by reaction at the aqueous interface.For instance, a complex acetate molecule such as cellulose triacetatemay be hydrolyzed in the vicinity of the interface to produce aceticacid. As indicated previously, a molecule of acetic anhydride may reactwith a molecule of water to produce two molecules of acetic acid. Theacetic acid produced would then be diluted by the body fluids to providethe desired suitable therapeutic concentration. Likewise, if glacialacetic acid is used as the active ingredient, it is diluted at theinterface by body fluids to form a therapeutically useful concentrationof aqueous acetic acid. Such active components capable of producingacetic acid of therapeutic utility are called herein pro-aceticcomponents.

Acetic anhydride and glacial acetic acid are preferred materials to beused in substantially non-aqueous mediums. Acetic acid in aqueoussolution in the form of concentrated acetic acid solutions e. g. aceticacid may be used provided they are dispersed or dissolved in asubstantially non-aqueous medium so that :a therapeutically usefulconcentration -of acetic acid may be produced at the tissue interface.As the amount of water increases in a substantially non-aqueous system,the physical stability of the system generally decreases. Dispersingagents such as soaps, detergents, and the like may be added to aid indispersing an aqueous material through a substantially non-aqueousmedium. Also, if a substance such as lanolin is part of the composition,more water in admixture with the acid can be tolerated. But as indicatedabove, the preferred embodiment of the invention minimizes the amount ofwater present in the substantially nonaqueous composition containing apro-acetic component.

The pro-acetic component is used in a substantially non-aqueous topicalmedium, e. g. a medium suitable for topical application as to the humanepithelium. Such medium serves to control the rate of delivery of theactive component to the aqueous interface. The media should serve as areservoir for the pro-acetic component and permit its slow diffusion tothe aqueous interface. For instance, various grades of petrolatum may beemployed. If one desires a fluid or semi-fluid mass, a relatively lowviscosity, oily, material may be used, whereas, if a more solid mass isdesired, a highly viscous medium may be employed. Petrolatum is used todescribe a refined petroleum material having the general formulaCnH2n-l-2. These materials have melting points in the range of 38 to 54C. and they are sometimes called paraffin jellies. Specific fractionsmay be more suitable for a desired application than others. Forinstance, if a less fluid composition is desired, a higher meltingpetrolatum is used. Substantially anhydrous lanolin may also be used infor pro-acetic components.

compounding materials'of the kind here described. Lanolin has theproperty of promoting interreaction with an aqueous phase.

Thus, it is not meant to limit the main vehicle material to petrolatumtypes or to be limited in the ways of incorporating aqueous acetic acidproducing materials in the substantially non-aqueous medium. Glycerideoils have been used particularly olive, corn and peanut. Of these,medicinal olive oil has been most extensively used because of its purityand known quality. The vegetable oils are theglycerides of palmitic,stearic, oleic, arachidic, hypogalic, lignoceric, linolic, and the likeand these areparticularly suited for use desirably with othersubstantially anhydrous Oils to hold acetic anhydride to formcompositions which are therapeutically useful. Tallow is also availablein many degrees of refinement and such materials can be usedadvantageously. Tallow has an ability toxhold: substantial quantities of.both' acetic anhydride and glacialacetic acid in apparentsolution andpermits slow diifusion of. the pro-acetic component to anaqueousinterface where therapeutically useful concentrationsof aceticacid are formed.

The polyethylene glycols e. g. Carbowaxes, and such other non-aqueousmaterials, therapeutically suitable, may be used, as components of thesubstantially water insoluble composition. The term Carbowax is used to.describe compounds of the dihydroxy-ether typehaving the, generalformula HOCH2(CH2OCH)7LCH2OH. They vary in degree of solidness andhygroscopicity. Individual commercially available compounds identifiedin terms of molecular weight and melting point ranges include:

IVI. W. M. P., C.

acetic components. Thus, glacial acetic acid can be contained in glycolcontaining compositions without reaction. Acetic anhydride, on the otherhand, tends to react with glycol and similar types to form esters. Thistendency increases with temperature, concentration and is influenced bycertain catalysts. Propylene glycol may be used as a solvent aid inacetic anhydride and/or glacial aceticpetrolatumpropylene glycolcompositions without apparent reaction to form esters. Both .aceticanhydride and glacial acetic acid are unreactive towards the petrolatumtype media. Esters, if formed, can be present as a source of acetic acidby hydrolysis at the interface. Other glycols and their esters such asacetic esters which have a solvent action on pro-acetic compounds andare substantially water insoluble also may be used in compositions ofthisinvention as vehicles Propylene glycol diacetate maybe used as acooperative solvent agent in substantially water insoluble compositionsand also it may, on slow, partial, hydrolysis, at the aqueous interface,

.serve as a pro-acetic component.

fter insoluble and capable of holding a supply of the acetic is I acidproducing agent and permit diitusion of this agent to the interfacewhere an aqueous acetic acid solution of the proper concentration can beformed by reaction and/or dilution.

The non-aqueous topical medium may desirably be a solvent tor thepro-acetic component or a more active topically suitable solvent,desirably liquid, may be used as illustrated above to enhance solutionof the proacetic component in the topical medium. The ultimatecomposition employed may be of any desired consistency as liquid,unctuous, solid, etc. and the application may also be made in aerosoltypes of compositions and other compositions for application in bodycavities by vapor or spray transfer or" active ingredients to the tissuesurface. Various mediums and adjuvants may be mixed to adjust theproperties of the composition. One or more of the pro-acetic componentsmay be utilized with any combination of mediums so that two or more ofany of the :sp'ecific components'set forth may be'mixed to produce avariety of physical 'propertiesas desired.

The ranges of proportions of components even of the pro-acetic componentdepend'on the nature of the composition, the solvent and othercomponents, their ratios, and the conditions under which the compositionis used. Various considerations bearing onthe question of proportionsare givenlbelow. One of themprincipal objects of the present inventionis the employment of what-are normally considered lethal:materials, for.therapeutic purposes. In our copending application, Serial No. 164,028,

now U. S. Patent No. 2,726,982, filed May 24, 1950, entitled HydrousGels, under the conditions there set forth, an upper limit ofapproximately 4% aqueous acetic acid is claimed to be the maximum thatcan be tolerated in contact with a wound to inhibit bacterial growthwhile still permitting epithelial growth. Compositions containing 10%acetic anhydride in a petrolatum, parawax, olive .oil composition havebeen successfully employed. -If

the composition contain suflicient diffusion inhibiting material, suchas parawax, the rate of deliverance of pro-acetic component can becontrolled to obtain a desired therapeutic concentration of aqueousacetic acid at the tissue interface while still permitting the use of arelatively high concentration of pro-acetic component in thesubstantially non-aqueous phase. Even 20% may not be unreasonable in arelatively slow diffusing system. One such highly concentratedcomposition, was made by blending 30 grams of Esso parawax, 30 grams ofyellow petrolatum, 48 grams of olive oil, and 12 grams of aceticanhydride. The olive oil and petrolatum were melted together and theacetic anhydride added thereto with efficient stirring. This was thenblended with the melted parawax and the resulting mass allowed to cool.In use, this relatively solid composition was melted and used toimpregnate gauze bandage in which form it handles nicely.

The oil, wax, etc., proportions are not critical but the The followingexamples will illustrate the invention, parts being by weight unlessotherwise indicated.

5 0.1 parts "acetic anhydride 290.8 parts medicinal olive oil 2,265.0parts petrolatum (Vaseline) Any method of compounding the components maybe used. The following is exemplary. The acetic anhydride is firstdissolved .in theolive oil and this solution added with stirring to themeltedpetrolatum. A homogeneous preparation of good consistency results.This has been usedv in various ways, generally, with. gauzeas is donewith ordinary Vaseline or petrolatum.

avsasos Percent Percent Petrolatum Esso parawnx A 100 B- 95 C 90 D. 85

Base compositions A, B, C, and D are progressively less mobile and whenused as part of the non-aqueous carrier for active ingredient, offerprogressively greater resistance to diffusion and thus this permits oneto exercise a degree of control of rate of deliverance of activeingredient to the aqueous interface.

Four compositions were prepared using base stock A (pure yellowpetrolatum).

Percent grams A grams R acetic anhydride net Likewise, four compositionswere prepared using base stock B (95% petrolatum and 5% Esso parawax).

Percent grams B grams R acetic anhydride net In the same waypreparations have been made with base stocks C and D.

Also, selected preparations have been made wherein glacial acetic acidwas substituted for acetic anhydride in the preparation of an activeingredient containing base solution.

III

Lanolin containing compositions are illustrated by the followingconsisting of a blend of petrolatum (85 grams), anhydrous lanolin (15grams), and 3.5 grams of the olive oil base stock containing 14.9%acetic anhydride. The resulting composition contained 0.50% aceticanhydride and has a desirable physical nature for therapeutic use.

Peanut oil may be used in place of medicinal olive oil in thecompositions given above with encouraging results as a primary solventfor acetic anhydride.

Compositions consisting solely of an oil such as olive oil and aceticanhydride have been used with demonstrated utility. Five percent aceticanhydride in olive oil has been used to treat scalp infections. Thepro-acetic component diffuses out of the oil and slowly hydrolyzes toform aqueous acetic acid. Compositions can vary widely and perfumes andother agents commonly used in such mixtures may be included. Spefificexamples are:

To 95 grams olive oil add 5 grams acetic anhydride and affect solutionby effective agitation.

To 50 grams olive oil add 5 grams acetic anhydride and affect solution.To this add 45 grams of liquid petroleum jelly normally liquid at roomtemperature.

This type of composition by its anti-bacterial action may also be usedto improve the function of scalp cosmetics by addition thereto. Theother glyceride oils may be used in such compositions in lieu of oliveoil.

The Carbowax type compounds are particularly suited to be a part of asubstantially non-aqueous substantially water insoluble medium carryingthe pro-acetic component. Carbowax compounds are unctuous wax-likesolids having excellent physical and physicalchemical characteristicsfor the purpose here described.

The following compositions illustrate methods of using Carbowaxes:

VII

10 grams of Esso parawax and grams of Carbowax 1540 were melted togetherand thoroughly mixed. To this blend was added 5 grams of glacial aceticacid and on cooling a composition of this invention is obtained. Theparawax tends to make the composition less fluid at body temperature andalso slows down the rate of diffusion of pro-acetic component to theaqueous interface.

As a second example of Carbowax containing compositions, the followingis cited:

VIII

10 grams olive oil or other glyceride oil and 80 grams of Carbowax 4000were melted together and 10 grams of glacial acetic acid added withstirring. The mass on cooling provides therapeutic concentrations ofaqueous acetic acid at an aqueous interface by the slow diffusion of thepro-acetic component to the point of use.

Substantially non-aqueous compositions substantially insoluble in watercarrying a pro-acetic component can be formed into a fine mist and assuch can be used to disinfect air and thereby control air borneinfectious agents. This discovery makes it possible to use compositionsof this invention for a variety of purposes.

In animal husbandry one often seeks to control the spread of infectionfrom one animal to another. Disinfection of the air in the confiningarea is possible by fine spray application. Also, breathing thepro-acetic spray may tend to assist recovery of the animal. A spraysuited to disinfect flocks confined in close quarters may for example bemade using peanut oil for carrying the pro-acetic component as follows:

95 parts of peanut oil and 5 parts of glacial acetic acid were blendedand used directly.

Pine oil and other perfumants may be used to disguise the odor andpossibly improve over-all utility. For instance:

parts peanut oil, 5 parts pine oil, and 5 parts glacial acetic acid weremixed to form a spray which is highly effective as an air disinfectingagent.

Similar compositions may be made using a pro-acetic component with anyof the usual vehicles employed in fine spray applied type compositionsparticularly those which are inert to the particular pro-aceticcomponent employed. Poppy seed and other vegetable oils may be used as avehicle for the proacetic component. Glycols hours.

.may be added as adjuvants for specific effects and/or solventingaction.

Compositions of the type described are particularly effective againstgram negative bacillae, pyocaneus, proteus, and E. coli. HemolyticStreptococcus and Staphylococcus aurcus are other typical organismscontrolled by compositions of this invention. Both skin and mucosalesions have been treated by these preparations. Infected infantileeczema with severe multiple ulceration have been cleared andepithelialized with this material. Foul infected severe second degreeburns have been cleared and healed rapidly with these compositions.Severe trauma to extremities with avulsion of the skin remained free ofinfection and have healed with this material. This material has beenusedas a packing in the maxillary sinus for 5 days without inhibitingepithelial growth and remainingfree of the foul odor usually resultingwhen-inert materials are used. it has also been .usedin many'noses as apacking for nose bleed andas a .splint to hold nasal fracture in place,without becoming infected.

stratetheeifectiveness of compounds described to inhibit bacterialgrowth. The pro-acetic component diffuses out of the substantially nonaqueous composition to form therapeutically useful concentrations ofacetic acid.

A mixture of yellow petrolatum with olive oil was used as a control andresults compared with an identical mixture containing 2% added aceticranhydride as the pro-acetic component. Filter paper discs wereimpregnated with one cc. each of the control blank and the pro-aceticcontaining composition. These impregnated discs were applied to thesurface of heavily streaked cultures of several organisms and incubatedfor 48 Examination of the cultures clearly showed a ring of clear mediaaround the disc containing the proacetic component. The controlcomposition impregnated discs show heavy growth of organisms up to andeven under the disc itself.

The following series of experiments are presented to demonstrate thefacts in regard to the actual diffusion of .platesdemonstratethis-action. However, to further establish the facts a seriesofdiffusion experiments whereby the production of acetic acid at theinterface was measured as a function of time by the movement of a pHfront through a-column of a 2% C. M. C. gel containing chlorphenol redas an indicator. Chlorphenol red changes color between 5.8 and l'5.2'pH.A second set of identical experiments-were carried out using bromthymolblue which changes at a pH of 6.0.

10 cc. portions of the C.- M. C. gel containing an indicator were placedin 10 mm. tubes and 5 cc. of proacetic (2% acetic anhydride) containingsubstantially non aqueous composition placed on top. The tubes weremaintained at 70 F. and the pH front observed as a 1Carboxyinethylcellulose.

solvent-vehicle is petrolaturn.

function of time. Two types of petrolatum were used and the experimentsrun in quadruplicate. For convenience, the information is tabulated.

Penetration mm. 5.2 Penetration-mm.-6.0

The-above data, when plotted indicate that the 6.0 pH front moved 40 mm.in 50 hours and the 5.2 pH front moved 26 mm. in 50 hours. The relativeslopes of the curves between 10 and 50 hours indicate that the 6.0 pHfront moves 1.57 times faster than the 5.2 pH front. These data provebeyond reasonable doubt that the pro-acetic component moved out-of thesubstantially non-aqueous mediumand diflused through an adjacent aqueousmedium. Likewise when such substantiallynon aqueous compositionscontaining a pro-acetic agentare used for therapeutic purposes, a usefulconcentration of acetic acid is produced at the interface. Withinexperimental error, there was no difference in the rate of diffusioncaused by substituting yellow petrolatum for-the more highly refinedwhite variety. For some applications the yellow is preferred in that ithas more fibre and is less fluid at body temperature.

Having thus set forth our invention, we claim:

1. A substantially anhydrous topical composition for the promotion ofepithelialization by the control of antia bacterial action consisting ofan acetic component selected from the group consisting of glacial aceticacid and acetic anhydride in a non-aqueous solvent-vehicle selected fromthe group consisting of glyceride oils, propylene glycols, polyethyleneglycols, and petrolatum, and mixtures thereof, the acetic componentbeing present in proportions from 0.5% to 20% by weight, so as toproduce therapeutic action at tissue interface.

2. The topical composition of claim 1 acetic component is glacial aceticacid.

3. The topical composition of claim 1 acetic component is aceticanhydride.

4. The topical composition of claim 1 solvent-vehicle is a glycerideoil.

5. The topical composition of claim 1 solvent-vehicle is a propyleneglycol.

6. The topical composition of claim 1 solvent-vehicle is a polyethyleneglycol.

7. The topical composition of claim 1 in which the in which the in whichthe in which the inwh'ich' the in" which" the References tCited inthefile of this patent UNITED STATES PATENTS Knaggs Nov.-8, 21887 OTHERREFERENCES Lesser: Drug-and Cosmetic Ind 'January i949; v61 64, No. l,p. 44-.

Am. Iour. of Pharm., vol. 119, pp. 393 and 394.

Pharmaceutical Formulas, The Chemist and Driiggist,

4 London. 1944, page 660.

7 Hopkins: Tour. of Investigative -Derinatology,"'Augiist 1946,pp.171-173.

1. A SUBSTANTIALLY ANHYDROUS TOPICAL COMPOSITION FOR THE PROMOTION OFEPITHELIALIZATION BY THE CONTROL OF ANITBACTERIAL ACTION CONSISTING OFAN ACETIC COMPONENT SELECTED FROM THE GROUP CONSISTING OF GLACIAL ACETICACID AND ACETIC ANHYDRIDE IN A NON-AQUEOUS SOLVENT-VEHICLE SELECTED FROMTHE GROUP CONSISTING OF GLYCERIDE OILS, PROPYLENE GLYCOLS, POLYETHYLENEGLYCOLS, AND PETROLATUM, AND MIXTURES THEREOF, THE ACETIC COMPONENTBEING PRESENT IN PROPORTIONS FROM 0.5% TO 20% BY WEIGHT, SO AS TOPRODUCE THERAPEUTIC ACTION AT TISSUE INTERFACE.